The Tryptophan Catabolite or Kynurenine Pathway’s Role in Major Depression

Kynurenine or tryptophan catabolite (TRYCAT) pathway contributes to the pathophysiology of major depression disorder (MDD) and major depressive episodes (MDE) in bipolar disorder and suicidal behaviors. The consequences of the overactivation of this pathway large reduced tryptophan (TRP) levels in peripheral blood and the CNS and increased levels of neurotoxic TRYCATs including kynurenine (KYN), 3-hydroxy kynurenine (3HK), quinolinic acid (QA), xanthurenic acid (XA), and picolinic acid (PA). However, other TRYCATs are protective, such as kynurenic acid (KA) and anthranilic acid (AA). Inflammation and cell-mediated immune activation along with oxidative and nitrosative stress (O&NS) may stimulate the first and rate-limiting enzyme of this pathway, namely indoleamine-2,3-dioxygenase (IDO). Therefore, during depression, balancing neuroprotective versus neurotoxic TRYCATs and balancing activation of the immune response system (IRS) versus the compensatory immune response system is crucial for achieving better treatment outcomes. Furthermore, targeting the causes of TRYCAT pathway activation (immune activation and O&NS) is probably the most effective strategy to treat depression. In the present review, we aim to provide a comprehensive explanation of the impact of TRYCATs in terms of pathophysiology and treatment of MDD and MDE.

pH-Responsive N^C-Cyclometalated Iridium(III) Complexes: Synthesis, Photophysical Properties, Computational Results, and Bioimaging Application

Herein we report four [Ir(N^C)2(L^L)]n+, n = 0,1 complexes (1–4) containing cyclometallated N^C ligand (N^CH = 1-phenyl-2-(4-(pyridin-2-yl)phenyl)-1H-phenanthro[9,10-d]imidazole) and various bidentate L^L ligands (picolinic acid (1), 2,2′-bipyridine (2), [2,2′-bipyridine]-4,4′-dicarboxylic acid (3), and sodium 4,4′,4″,4‴-(1,2-phenylenebis(phosphanetriyl))tetrabenzenesulfonate (4). The N^CH ligand precursor and iridium complexes 1–4 were synthesized in good yield and characterized using chemical analysis, ESI mass spectrometry, and NMR spectroscopy. The solid-state structure of 2 was also determined by XRD analysis. The complexes display moderate to strong phosphorescence in the 550–670 nm range with the quantum yields up to 30% and lifetimes of the excited state up to 60 µs in deoxygenated solution. Emission properties of 1–4 and N^CH are strongly pH-dependent to give considerable variations in excitation and emission profiles accompanied by changes in emission efficiency and dynamics of the excited state. Density functional theory (DFT) and time-dependent density functional theory (TD DFT) calculations made it possible to assign the nature of emissive excited states in both deprotonated and protonated forms of these molecules. The complexes 3 and 4 internalize into living CHO-K1 cells, localize in cytoplasmic vesicles, primarily in lysosomes and acidified endosomes, and demonstrate relatively low toxicity, showing more than 80% cells viability up to the concentration of 10 µM after 24 h incubation. Phosphorescence lifetime imaging microscopy (PLIM) experiments in these cells display lifetime distribution, the conversion of which into pH values using calibration curves gives the magnitudes of this parameter compatible with the physiologically relevant interval of the cell compartments pH.

Cytotoxic Effect of Ethanol Extract of Abrus precatorius Leaves on Raw 264.7 and SK-N-SH Cell lines

Aim: This study was aimed to investigate the cytotoxic effect of ethanol extract of Abrus precatorius. leaves on Raw 264.7 and SK-N-SH cell lines. Methodology: Soxhlet extraction was carried out using absolute alcohol and subsequently, the profiling of phytoconstituents of ethanol extract was performed by LC-MS analysis. Results: The results showed that the presence of anthocyanin, phenolic acid, carboxylic acid, amino acid and monoester in ethanol extract of Abrus precatorius. The phytoconstituents such as picolinic acid, N-Acetyl-DL-tryptophan, 3-Hydroxybenzoic acid, kuromanin, aflatoxin G2, monobutyl Phthalate, laurolactam, 4-Dodecylbenzenesulfonic acid, 4-Methoxycinnamic acid, caffeic acid and octyl decyl phthalate were found in ethanol extract. In addition to this, the cytotoxic effect of the ethanol extract was tested on Raw 264.7 and SK-N-SH cell lines using MTT assay. The cytotoxic study revealed that the ethanol extract of Abrus precatorius was non-toxic to Raw 264.7 cell, but it showed a toxic effect on human neuroblastoma cell line, SK-N-SH. Conclusion: In this study, it was observed that the ethanol extract of Abrus precatorius was non-toxic to Raw 264.7 cell line, but it exhibited strong inhibition on the viability of SK-N-SH cell line.

Mirror-Like Bright Al-Mn Coatings Electrodeposition from 1-Ethyl-3 Methylimidazolium Chloride-AlCl3-MnCl2 Ionic Liquids with Pyridine Derivatives

The effects of three pyridine derivative additives, 4-hydroxypyridine, 4-picolinic acid, and 4-cyanopyridine, on Al-Mn coatings were investigated in 1-ethyl-3-methylimidazolium chloride-AlCl3-MnCl2 (EMIC-AlCl3-MnCl2) ionic liquids. The smooth mirror-like bright Al-Mn coatings were obtained only in the EMIC-AlCl3-MnCl2 ionic liquids containing 4-cyanopyridine, while the matte Al-Mn coatings were electrodeposited from EMIC-AlCl3-MnCl2 without additives or containing either 4-hydroxypyridine or 4-picolinic acid. The scanning electron microscope and X-ray diffraction showed that the bright Al-Mn coatings consisted of nanocrystals and had a strong (200) preferential orientation, while the particle size of matte Al-Mn coatings were within the micron range. The brightening mechanism of 4-cyanopyridine is due to it being adsorbed onto the cathode to produce the combined effect of (1) generating an overpotential to promote Al-Mn nucleation; (2) inhibiting the growth of the deposited nuclei and enabling them grow preferentially, making the coating composed of nanocrystals and with a smooth surface. The brightening effect of 4-cyanopyridine on the Al-Mn coatings was far better than that of the 4-hydroxypyridine and the 4-picolinic acid. In addition, the bright Al-Mn coating was prepared in a bath with 6 mmol·L−1 4-cyanopyridine and displayed superior corrosion resistance relative to the matte coatings, which could be attributed to its unique nanocrystalline structure that increased the number of grain boundaries and accelerated the formation of the protective layer of the corrosion products.

Chronic Unpredictable Stress Alters Brain Tryptophan Metabolism and Impairs Working Memory in Mice without Causing Depression-Like Behaviour

Chronic stress is a well-known risk factor in major depressive disorder and disrupts the kynurenine and serotonin pathways of tryptophan metabolism. Here, we characterize the temporal central and peripheral changes in tryptophan metabolism and concomitant depressive-like behavioural phenotype induced during the progression of chronic unpredictable stress (CUS). Mice were exposed to 0, 10, 20, or 30 days of CUS followed by a panel of behavioural assays to determine depressive-like phenotypes. Immediately after behavioural testing, plasma and brain tissue were collected for metabolic analysis. While anhedonia-like and anxiety-like behaviours were unaffected by stress, nesting behaviour and cognitive deficits became apparent in response to CUS exposure. While CUS caused a transient reduction in circulating quinolinic acid, no other tryptophan metabolites significantly changed in response to CUS. In the brain, tryptophan, kynurenine, picolinic acid, and 5-hydroxyindoleacetic acid concentrations were significantly elevated in CUS-exposed mice compared with non-stress control animals, while kynurenic acid, xanthurenic acid, and serotonin decreased in CUS-exposed mice. Metabolic turnover of serotonin to the major metabolite 5-hydroxyindoleacetic acid was markedly increased in response to CUS. These results suggest that CUS impairs hippocampal-dependent working memory and enhances nascent nesting behaviour in C57BL/6J male mice, and these behaviours are associated with increased brain kynurenine pathway metabolism leading to accumulation of picolinic acid and a significant reduction in serotonin levels.

A novel derivative of picolinic acid induces endoplasmic reticulum stress-mediated apoptosis in human non-small cell lung cancer cells: synthesis, docking study, and anticancer activity

Thirteen new derivatives of picolinic acid (4–7) were designed and synthesized from the starting parent molecule, picolinic acid. The new compounds were characterized by ATR-FTIR, 1HNMR, and CHNS analysis. A molecular docking study was performed to evaluate the binding affinity of the synthesized compounds toward EGFR kinase domain that indicated occupation of the critical site of EGFR kinase pocket and excellent positioning of the compounds in the pocket. The cytotoxic activity of the compounds against two human cancer cell lines (A549 and MCF-7), the non-tumorigenic MCF10A cell line, and white blood cells (WBC) was evaluated using the MTT assay. Compound 5 showed anticancer activity against A549 lung cancer cells (IC50 = 99.93 µM) but not against MCF-7 breast cancer cells or normal cells. Compound 5 mediated cytotoxicity in A549 lung cancer cells by inducing apoptotic cell death, as suggested by fragmented nuclei after DAPI staining, and agarose gel electrophoresis. Moreover, compound 5 triggered the activation of caspases 3, 4 and 9. However, compound 5 treatment did not affect the release of cytochrome c from the mitochondria to the cytosol, as compared to the vehicle-treated control cells. Nevertheless, compound 5-treated cells reported greater release of smac/DIABLO to the cytosol. In the same context, both compound 5 and thapsigargin (specific inhibitor of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA)) enhanced eIF2 phosphorylation, reflecting the activation of the atypical ER stress pathway and the potential applicability of compound 5 in lung cancer treatment.